Arthropod maturation inhibitors

ABSTRACT

A number of terpenoid compounds and their epoxides were synthesized and found to prevent insect maturation when applied to insects in an immature stage of growth.

Schwarz et al.

ARTHROPOD MATURATION INHIBITORS Inventors: Meyer Schwarz, Kensington;Philip E. Sonnet, Bowie; Nobel Wakabayashi, New Carrollton, all of Md.

Assignee: The United States of America as represented by the Secretaryof Agriculture, Washington, DC.

Filed: Jan. 24, 1974 Appl. No.: 436,239

Related US. Application Data Division of Scr. No. 104,781, Jan. 7, 1971,Pat. No. 3,824,319.

[451 Sept. 9, 1975 [56] References Cited UNITED STATES PATENTS 3,671,5586/1972 Siddall et a1. 260/410.9 3,681,385 8/1972 Siddall 260/3273,706,733 12/1972 Henrick et a1. 260/327 E 3,824,319 7/1924 Schwarz eta1 424/278 OTHER PUBLICATIONS Borkovec, Insect Chemosterilants, V01. V11(1966), pp. 6163.

Primary ExaminerAlbert T. Meyers Assistant ExaminerLeonard SchenkmanAttorney, Agent, or Firm-M. Howard Silverstein; Max D. Hensley; WilliamE. Scott 57 ABSTRACT A number of terpenoid compounds and their epoxideswere synthesized and found to prevent insect maturation when applied toinsects in an immature stage of growth.

1 Claim, No Drawings ARTHROPOD MATURATION INHIBITORS A non-exclusive,irrevocable, royalty-free license in the invention herein described,throughout the world for all purposes of the United States Government,with the power to grant sublicenses for such purposes, is hereby grantedto the Government of the United States of America.

This is a division of application Ser. No. 104,781, filed Jan. 7, 1971,now US. Pat. No. 3,824,319.

This invention relates to the control of arthropods, especially insects,and more particularly to compounds and to the preparation of compoundswhich exhibit juvenile hormone activity by stimulation of larvaldevelopment and inhibition of metamorphosis.

In view of the concern throughout the world regarding the persistence ofmany insecticides and insecticide residues in our environment and thepotential hazard that these materials represent to human populations andfurthermore, in view of the fact that many species of insect pests havebecome resistant or immune to insecticides, the need for more selectiveagents to meet the problems is evident.

Many of the substances that exhibit juvenile hormone activity possess aterpenoid skeleton. These compounds such as farnesol methyl ether andthe juvenile hormone isolated from Hyalphora cecropia (L), methyl 10,1l-oxido-3 ,l l-dimethyl-7-ethyl trideca-2,6-dienoate, prevent theformation of sexually mature adults when applied at extremely low dosagelevels either topically to the insect in the pupal stage or as afumigant.

An object of this invention is to provide selective agents for controlof insect pests.

Another object is to provide new chemical compounds that prevent insectmaturation when applied to insects in an immature stage of growth.

In general, according to the present invention compounds of the generalformula in which Y is CH C=CH or CH C\-CH R R A is (i=CH or H n is anumber from 1 to 2 R is a straight chain alkyl group of from 1 to 2carbon atoms, a cycloalky] group, a phenyl group, a substituted with anexcess of an organo-lithium compound in which the organic group can bealkyl, alkinyl, alkynl or aryl. Compound 3 is then prepared byepoxidation of compound 1 with a peracid. Alternatively 1 may beprepared from using the Wadsworth-Emmons reaction (J. Amer. Chem. Soc.83, 1733 (1971) to produce The latter product may then be treated witheither an organo-Mg-halogen (Grignard reagent) or an organolithiumcompound to yield the desired compound 1 (the organic group is same asabove). Compounds 5 and 7 are prepared from the appropriate amines,

CICOOR (R as above), in the presence of a tertiary base such astriethylamine, which serves as a hydrogen chloride acceptor. Therequired amines are prepared by reduction of the oximes of thealdehydes.

and

3 using lithium aluminum hydride [Helv. Chim. Acta. 37,881 (1954)].

Again the epoxides 6 and 8 are readily prepared from the olefinicprecursors and 7 using peracid in an inert solvent. Compound is preparedby the condensation with a malonic acid derivative in the presence ofammonium acetate (J. Amer. Chem. Soc. 63, 3452 (1941). Again, '11 isobtained by epoxidation of 10 using a peracid.

The present invention provides a method for the control of insects,which comprises contacting the insects with one of thecompounds in asufficient amount to affeet the normal development of said insectsthrough their metamorphic stages. The materials may be applied to thesite of insect infestations by the same methods that are used tobroadcast conventional pesticides, that is, diluting them with inertsolid carriers or dissolving them in inert organic solvent or oil, oremulsifying them in water.

The following examples illustrate the present invention.

EXAMPLE 1 Preparation of 3,7-tridecadien-2-one, l l,l2-epoxy,4,8,12-tri-methyl. (Compound 3). To an ice cold suspension of sodiumhydride (2,4 g) in 200 ml N,N-dimethylformarnide' was added dropwisewith stirring while the reaction mixture is kept between 0 and 10C, 17.0gdiethyl cyanomethylphosphonate. When the hydrogen evolution ceased, thetemperature was kept below C and 19.0g geranyl acetone was addeddropwise.

The mixture was allowed to stand overnight and then it was added to 'alarge excess of cold water and extracted with hexane. The hexane extractwas washed with water, dried and evaporated. The residue wasfractionally distilled and yielded 15 g of farnesonitrile (bp 9497/0.2mm) which was converted to Compound 1 as follows: To an ice coldsolution of methyl magnesium iodide, prepared from magnesium (0.6 g) andmethyl iodide (4.5 g) in 100 ml anhydrous ethyl ether, was addeddropwise 5.4 g farnesonitrile. After the addition was complete thereaction mixture was refluxed for 2 hours, allowed to stand overnight,and then decomposed by dropwise addition of excess aqueous ammoniumchloride. The ether layer was evaporated and the residue was distilledto yield 3.0 g of Compound 1 bp 1051 l0/O.4 mm. Compound 1 (200 mg) wastreated at 0C with m-chloroperbenzoic acid (200 mg) in 10 ml methylenedichloride to yield compound 3 after extraction of the m-chlorobenzoicacid with dilute aqueous sodium carbonate and removal of the methylenedichloride. The resultant product is highly active against many insectspecies. Compound 3 can be further purified by distillation, gas-liquidor liquid-liquid chromatography. These processes however, do not enhancethe activity to a measurable extent.

EXAMPLE 2 Preparation of 3,7-Tetradecadien-2-one, l 1,12-epoxy-8-ethyl-4,l2-dimethyl. (Compound 4). Methyl- 3,1l-dimethyl-7-ethyltrideca-2,6,10-tricnoate (Braun, et al., J. Econ.Entomol. 61, 866 (1968) (2 g) was sa- 4 ponified with 1.5 g KOH in 50ml. ethanol. The acid was isolated from the reaction mixture byacidification and extraction with ether. An ether solution of the acid 1g) was treated with an excess of methyl lithium in hexane (5 ml of a 1.6molar solution). The ketone, Compound 2 (0.5 g), was obtained after thereaction mixture was decomposed with an aqueous solution of ammoniumchloride, followed by evaporation of the ether and moleculardistillation (bath)/O.5 mm). Epoxidation and workup, as described inexample 1, yielded Compound 4 which had extremely high juvenile hormoneactivity.

EXAMPLE 3 Preparation of carbamic acid, 3,7-dimethyl-6,7- epoxy-ethylester. (Compound 8). 3,7-Dimethyloct-6- enal (15.4 g) in 50 ml ethylalchohol was added to a solution of hydroxylamine hydrochloride (7 g)and sodium carbonate (5 g) in 25 ml of water. The mixture was heated onthe steambath for 15 minutes and then allowed to cool. Addition of anexcess of water yielded 3,7-dimethyl-oct-6-enal oxime as an oil. The oilwas extracted with ether and the organic layer dried and evaporated. Theresidue was added dropwise to a solution of lithium aluminum hydride(3.8 g) in 380 ml anhydrous ethyl ether. After refluxing overnight an:additional quantity of lithium aluminum hydride; (0.78 g) was added tocomplete the reduction. Decomposition of the reaction mixture withexcess aqueous sodium hydroxide (200 ml of 10% solution), separation ofthe ether layer, and distillation yielded 3,7-dimethyloct-6-enyl amine(10 g) bp 60/0.5 mm). To an ice cold solution of this amine 1.5 g) andtriethylamine 1.1 g) in ether (25 ml) was added dropwise a solution ofethyl chloroformate (1.1 g) in ether 10 ml). The reaction mixture wasallowed to stand overnight at room temperature. The triethylamiriehydrochloride was filtered off and the other solution washed with water,dilute hydrochloric acid, and again with water. The ether solution wasdried and evaporated and the residue distilled to yield 2 I g carbamicacid (3,7-dimethyl-6Foctenyl)-, ethyl ester (Compound 7), bp l02l03/0..lmm. The ester was epoxidized as described in the previous examples toyield VII. The crude reaction product can be readily purified bychromatography using neutral activated alumina.

EXAMPLE 4 Synthesis of 2 6-dodecadienoic acid, 2-cyano-l0,1 ldimethyl-,methyl ester (Compound 1 1). Geranyl acetone 10 g), methyl cyano acetate(6 g), ammonium acetate (2 g) and acetic acid (1 ml) were refluxed in200 ml benzene using a Dean-Stark water separator. After 2 hours ofrefluxing, one additional gram of ammonium acetate was added and therefluxing continued for 2 additiinal hours. The solution was cooled,washed with water and dried and then the solvent was removed. Theresidue was distilled to yield 2,6,l0-dodecatrienoic acid 2-cyano-3,7,1l-trimethyl-, methyl ester l l g), bp 130/.1 mm (Compound 10).Epoxidation of the above product as described previously yielded thecompound ll.

EXAMPLE 5 Malononitrile 1,5 ,9-trimethyl-8,9-epoxydec-4-enylidene)(Compound 12). A solution of geranyl acetone (10 g), malononitrile (4g), ammonium acetate (.5 g) and acetic acid (0.5 g) is refluxed, using aDean-Stark trap for 1 hour. The reaction mixture was allowed tornalononitrile-(1,5,9-trimethyl. decadi-4,8-enylidene) cool, then it waswashed with water and dried and the I (,9 g); bp '1 20 -l25/.3 mm.Epoxydation of the above benzene removed. The residue was distilled toyield as describedprevious'ly yielded compound 12.

TABLE 1 Juvenile Hormone Activity of Representative Compounds onTenehrio molitor pupae Minimum weight (in pg) of compound needed whenapplied topically to pupae to make the resultant mature insect Compoundincapable of reproduction TABLE l-continued Juvenile Hormone Activity ofRepresentative Compounds on Tenehrio molitor pupae Minimum weight (in g)of compound needed when applied topically to pupae to make the resultantmature insect incapable of reproduction Compound II N o 8 o H ().I

ll o 9. O a a (Mp no. coocH C N l l o C OOC H 3 OJ l2. C N

We claim: 3 3 1. A method of preventing the maturation of Te- CHC=CH(CH) i i v :i 2 2 2 2 \COOCH nebrio molitor pupae comprisingapplying to said pupae an effective maturation inhibiting amount of a'compound of the formula

1. A METHOD OF PREVENTING THE MATURATION OF TENEBRIO MOLITOR PUPAECOMPRISING APPLYING TO SAID PUPAE AN EFFECTIVE MATURATION INHIBITINGAMOUNT OF A COMPOUND OF THE FORMULA